This invention relates generally to amination of nitrogen-containing heterocycles by alkali metal amides, and in particular to a significant discovery with respect to the time-honored Chichibabin amination reaction.
In 1914, Chichibabin and Seide first reported that a-picoline, or more commonly 2-methypyridine, underwent direct amination in the free a-position on the ring when treated with sodium amide in toluene at elevated temperatures. Chichibabin and Seide, J. Russ. Phys. Chem. Soc., 46, 1216 (1914). This reaction was later extended by Chichibabin and his contemporaries to amination of many pyridine, quinoline and isoquinoline bases. It has since been recognized as one of the more important and influential developments in pyridine chemistry, so much so that the reaction itself has become synonymous with the name of its discoverer. Its commercial importance should also not be discounted as, for example, the 2-amino amination product of pyridine itself has become an enormously important and useful starting material for further synthesis in many areas.
The Chichibabin reaction has been the subject of much study and comment through the years, both as to scope and as to the mechanism of the amination. For example, although first carried out in toluene, the reaction has since been carried out in other aprotic solvents of which dialkylanilines, liquid paraffin and other hydrocarbons such as benzene, xylene, cumene, mesitylene and petroleum fractions are most common. Similarly, although first accomplished using sodium amide, or more commonly sodamide, the reaction has since been carried out with other metal amides such as potassium amide, barium amide, etc., particularly when using low temperatures and long reaction times in attempting to slow the reaction to study the mechanism of its amination process. The Chichibabin mechanism remains one of the least understood nucleophilic substitution reactions in heterocyclic chemistry owing to the difficulty in handling the alkali metal amides and in studying kinetics of a process which takes Place under heterogeneous conditions at high temperatures. Classicly, those conditions have included heating the mixture at atmospheric pressure and at temperatures between about 100.degree.-200.degree. C. Another characteristic feature has been the evolution of hydrogen gas and ammonia gas which signals the start of the reaction and identifies its progress toward completion. Novikov, Pozharskii & Doron'kin, Translated from Khim. Geterotsikl. Soedin., No. 2, 244 (1976); Levitt & Levitt. Chem. & Ind., 1621 (1963).
The base compound which undergoes amination has also received much study. Reports document the amination of mono and diazines such as pyridines, quinolines, isoquinolines, benzoquinolines, phenanthridines, acridines, benzimidazoles, quinazolines, naphthyridines, pyramidines, pyrazines and other heterocyclic systems. Reactions related to the Chichibabin amination have also been studied which are not heterocycles, but have a N=CH group such as Schiff bases. Pozharskii, Simonov and Doron'kin, Russ. Chem. Rev., 47, 1042 (1978), Translated from Uspekhi Khim., 47, 1933 (1978). The result of these efforts is that the predictability of Chichibabin aminations is thought to be high for a given base compound, as are the expected product or products of the reaction. Although such certainty is helpful, situations arise where a partial or complete change in the Chichibabin result is desirable. For example, expected products may not be desired, or new products may be wanted, or isomer ratios may be preferably reversed.
An important example of this last category is the case of 3-substituted pyridine bases, and particularly 3-alkyl derivatives, which are known to undergo Chichibabin amination to produce predominantly 2-amino-3-alkylpyridine ("2,3-isomer") and to a much lesser extent 2-amino-5-alkylpyridine ("2,5-isomer"). The amination of 3-methylpyridine, also known as 3- or .beta.-picoline, is an excellent example, which reportedly yields the 2,3- and 2,5-isomers in a ratio of about 10.5:1. Abramovitch, Advan. Heterocycl. Chem.. 6, 294 (1966); Abramovitch Helmer and Saha, Chem. & Ind., 659 (1964); Abramovitch, Helmer and Saha, Can. J. Chem., 43, 727 (1965). This is highly unfortunate as the 2,5-isomers are much preferred because of their usefulness as starting materials and intermediates for the preparation of herbicides, insecticides and pharmaceuticals. Chemical manufactures are hard-pressed to meet the demand for 2,5-products since they are left with very large quantities of largely unusable 2,3-isomer at this time. Understandably, there is thus a substantial need to change the classic Chichibabin amination in this case in a way that improves the yield of these 2,5-products, of which 2-amino-5-methylpyridine is most preferred, at least at this time.
Notwithstanding the many years of study of the Chichibabin reaction, no significant breakthrough has been reported which teaches or suggests a methodology to change the reaction's classic mechanism or its anticipated results given a particular heterocyclic base compound. That is, not until now.